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Proc Natl Acad Sci U S A. 2007 May 22;104(21):9007-11. Epub 2007 May 11.

Fetal gene therapy of alpha-thalassemia in a mouse model.

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  • 1Cardiovascular Research Institute, Institute of Human Genetics and Department of Medicine, University of California, San Francisco, CA 94143, USA.

Abstract

Fetuses with homozygous alpha-thalassemia usually die at the third trimester of pregnancy or soon after birth. Hence, the disease could potentially be a target for fetal gene therapy. We have previously established a mouse model of alpha-thalassemia. These mice mimic the human alpha-thalassemic conditions and can be used as preclinical models for fetal gene therapy. We tested a lentiviral vector containing the HS 2, 3, and 4 of the beta-LCR, a central polypurine tract element, and the beta-globin gene promoter directing either the EGFP or the human alpha-globin gene. We showed that the GFP expression was erythroid-specific and detected in BFU-E colonies and the erythroid progenies of CFU-GEMM. For in utero gene delivery, we did yolk sac vessel injection at midgestation of mouse embryos. The recipient mice were analyzed after birth for human alpha-globin gene expression. In the newborn, human alpha-globin gene expression was detected in the liver, spleen, and peripheral blood. The human alpha-globin gene expression was at the peak at 3-4 months, when it reached 20% in some recipients. However, the expression declined at 7 months. Colony-forming assays in these mice showed low abundance of the transduced human alpha-globin gene in their BFU-E and CFU-GEMM and the lack of its transcript. Thus, lentiviral vectors can be an effective vehicle for delivering the human alpha-globin gene into erythroid cells in utero, but, in the mouse model, delivery at late midgestation could not transduce hematopoietic stem cells adequately to sustain gene expression.

PMID:
17496141
[PubMed - indexed for MEDLINE]
PMCID:
PMC1885618
Free PMC Article

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